There are several strategies now available for the catalytic enantioselective
construction of oxygenated and aminated stereogenic centers. Catalytic processes
for the enantioselective construction of alkylated stereogenic centers are just
starting to appear. In general, investigators have approached this problem by
reacting a prochiral electrophile with a chiral catalyst and a nucleophile.
There are three variables that are useful to consider: the nucleophile, the
catalyst, and the substituents at the reacting center.

One of the first such reactions to be reduced to practice was the addition of
malonate to cinnamyl carbonate 1. The current state of the art is
illustrated by a recent contribution (Org. Lett.2005, 7,
1621.
)
from
Alexandre Alexakis at the University of Geneva, in which the Ir catalyst was
further optimized. The coupling proceeded with 98:2 regioselectivity in the
desired sense.

In general, aryl substituted stereogenic centers such as that of 2 are
the easiest to form with high enantioselectivity. Thus, when Kiyoshi Tomioka and
co-workers of Kyoto University investigated (J. Org. Chem.2005,
70, 297.
)
the conjugate addition of dialkyl zinc reagents to α,β-unsaturated
aldehydes, they began with substrates such as 3. They found that when the
aldehyde was replaced by a sterically-demanding sulfonyl imine, Cu*-mediated
conjugate addition was efficient. They chose to analyze the intermediate
enantiomerically-enriched aldehyde as the corresponding alcohol 4. The
ee’s are modest by current standards.

Alkyl zinc halides are more readily available than dialkyl zincs. Gregory C.
Fu of MIT recently described (J. Am. Chem. Soc.2005, 127,
4594.
)
the
Ni*-mediated coupling of such reagents to racemic α-bromoamides such as 5,
to give the highly enantiomerically-enriched products such as 7. This is
the functional equivalent of catalytic enantioselective alkylation of the amide
enolate. The amide 7 is easily reduced to the primary alcohol 8.
The authors note that the alkyl zinc halides must be freshly prepared - a
commercial reagent did not work.

Conjugate addition is complementary to α-alkylation. Ben L. Feringa of the
University of Groningen has described (Angew. Chem. Int. Ed.2005,
44, 2752.
)
the
catalytic enantioselective addition of Grignard reagents to α,β-unsaturated
esters such as 9. This procedure works well with a wide range of esters
and Grignard reagents.

Some trialkyl aluminum reagents are commercially available. Alexandre
Alexakis of the University of Geneva has also reported (Tetrahedron Lett.
2005,
46, 1529.
)
the conjugate addition of Me3Al to nitro alkenes such as
11. The product nitro compounds can be converted into acids without
racemization. Carreira previously (2005, June 20) has shown that nitro compounds such
as
12 can also be converted into the corresponding nitriles without
epimerization.

One could imagine that alkylated stereogenic centers could also be
constructed by the enantioselective reduction of trisubstituted alkenes. David
W. C. MacMillan of Caltech has now (J. Am. Chem. Soc.2005, 127,
32.
)
reduced
this to practice. Using Hantsch ester 15 and an organocatalyst, geometric
mixtures of α,β-unsaturated aldehydes such as 14 are reduced with
remarkable enantiomeric excess.